The innate and adaptive arms of the immune system regulate the clearance of infectious organisms by effector mechanisms induced through a complex set of receptor/ligand interactions between a number of different cell types. The molecular mechanism by which most receptors induce their biologic effects is through a process of receptor aggregation and subsequent activation of intracellular enzymes, such as protein kinases, that are associated with the cytoplasmic tails of the receptors. The activation of these enzymes in turn initiate signaling cascades that regulate cellular activation, proliferation, differentiation, and effector function. However, there are a number of receptors that cannot directly activate the intracellular signal transduction machinery, yet are capable of modulating cellular responses. Interestingly, many of these unusual receptors have ecto-enzymatic properties and can be organized into extracellular metabolic pathways such that the product of one ecto- enzymatic reaction serves as the substrate for the next reaction. One example of such an ecto-enzyme is the NAD glycohydrolase, CD38. CD38 utilizes the dinucleotide, NAD, as a substrate and catalyzes the production of several metabolites that can be directly utilized by cells, used as agonists for other signaling receptors, or utilized by other extracellular enzymes to generate additional metabolites. In addition to its enzymatic properties, CD38 has also has been shown to regulate a number of functions in vitro including lymphocyte adhesion, activation, proliferation, apoptosis, and effector function. CD38 plays an important role in vivo as well, since mice that are genetically deficient for CD38 cannot mount a protective response to bacterial pathogens such as Streptococcus pneumoniae. In addition, CD38-deficient animals make poor primary humoral immune response to experimental antigens and are unable to mount a productive humoral memory response. Although CD38 clearly regulates both innate and acquired immune responses, the molecular mechanism by which CD38 or other ecto-enzymes modulate immune responses is unknown. Therefore, the goal of this proposal is to identify the cellular and molecular mechanisms by which CD38 regulates the immune response to foreign antigens. The specific aims are designed to test the hypothesis that the extracellular enzymatic activity of CD38 is required for the generation of productive humoral and innate immune responses. These experiments will provide a framework for understanding the elusive role of ecto-enzymes such as CD38 in the generation and maintenance of protective immunity.